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CONTENT="Aromaticity Detection in Marvin">
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<h1>Aromaticity Detection</h1>

<h2>Which molecules are aromatic?</h2>
<p>
An aromatic molecule is one in which electrons
form a continuous pi cloud above and below the 
circular arrangements of atoms.
In one representation these atoms are connected by
alternating single and double bonds.
Another representation is that of the circular pi bond, in which the 
electron density is evenly distributed through a pi bond 
above and below the ring.
The circulating pi electrons in a aromatic molecule generate significant 
local magnetic fields that can be detected by NMR techniques.
Aromatic molecules typically display enhanced chemical stability, compared to similar non-aromatic molecules.
</p>
<p>
This commonly seen model of aromatic rings was developed by 
Friedrich August Kekul&eacute; von Stradonitz and was first explained 
in quantum mechanical terms by Linus Pauling in the 1930s.
In 1931, Erich H&uuml;ckel devised the "4n+2" pi electron rule, 
valid for planar molecules with a single ring. 
Molecules having 4n+2 pi electrons (n &gt;= 0) are expected to be aromatic.
</p>

<h2> Methods </h2>
<p>
Two types of transformation to aromatic representation 
are implemented in Marvin, both are based on the H&uuml;ckel's 4n+2 rule.
</p>
<P>
All transformation methods work only in structures which are in 
non-aromatic representation. 
If the molecules are in partially aromatic form 
(containing any aromatic bond) the transformation method may fail.
</P>

<BLOCKQUOTE>
<h3><a class="anchor" NAME="basic">Basic aromaticity detection</a> </h3>
<P>
Process: locate the ring atoms in the molecule connected with 
single and double bonds respectively, sum the number of electrons and
if the H&uuml;ckel's rule is valid, then the ring is aromatic.
Ring systems are also checked.
</P>
<P>
There are some exceptions: 
</P>
<UL>
<LI>Where the double and single bonds are not sequential but 
the ring is aromatic. In this case the atom between single bonds 
has an orbit which takes part in the aromatic system. 
(Relevant atoms: N, O, P, S, As and Se when they can donate a free 
electron-pair to the aromatic system and B when it can donate a
molecule orbit without additional electron.) 
<LI>Rings with less than 5 members are not aromatic.
</UL>


<h3><a class="anchor" NAME="daylight_arom">General aromaticity detection</a> </h3>
<p>
The method is the same as used by Daylight.<br>
Locate the ring atoms in the molecule connected with 
single and double bonds respectively, sum the number of electrons and
if the H&uuml;ckel's rule is valid, then the ring is aromatic.
Ring systems are also checked. The atoms at the generated ring system 
may not form a continuous ring like in benzo[de]chromene 
(SMILES: O1C=CC2=CC=CC3=CC=CC1=C23)
where all atoms of the molecule are in the ring system generated from the 
three 6 membered ring.
</p>
<P>
There are some exceptions: 
</P>
<UL>
<LI>Oxygen and sulfur can share a pair of pi-electrons. 
<LI>Nitrogen can also share a pair of pi-electrons, if it has three ligands, 
otherwise the sp2 nitrogen shares just one electron (as in pyridine). 
<LI>An exocyclic double bond to an electronegative atom takes out 
one shared pi-electron from the cycle, as in 2-pyridone or coumarin.
</UL>

<h3><a class="anchor" NAME="loose">Loose aromaticity detection</a> </h3>
<p>
The following ring systems are interpreted as aromatic:<br>
<UL>
<LI> Five-membered rings such as the structures shown below:<br>
(Where: A = any atom except hydrogen, Q = any atom except H or C)<br>
<IMG SRC="14.png" ALT="five-membered1">
<IMG SRC="15.png" ALT="five-membered2">

<LI> Six-membered rings that can be drawn as alternating single and double bonds:<br>
<IMG SRC="16.png" ALT="benzene">
<IMG SRC="17.png" ALT="pyridine">
<IMG SRC="18.png" ALT="naphtalene">
<IMG SRC="19.png" ALT="phentanthrene">

<LI> Perimeter bonds in azulenes:<br>
<IMG SRC="20.png" ALT="azulene">
</UL>

</BLOCKQUOTE>

<h2>Differences between the Basic and General methods</h2>
<P>
The two method approach the question differently.
The general method tries to incorporate mesomeric, 
tautomeric rearrangement, as in 2-pyridone, while the basic method does not. 
In the basic method the external double bond breaks the formation of
aromatic ring.
</P>
<P>
The 2-pirydone is aromatic due to its mesomeric rearrangement:<br>
<IMG SRC="pyridone_mesomer.png" ALT="pyridone mesomer">
</P>
<P>
The following molecules will give different results depending upon the method applied.
</P>
<table border="0" cellspacing="0" cellpadding="5" class="grid">
<!--<TR>
<TH>Molecule in aliphatic form</TH>
<TH>Basic aromatization</TH>
<TH>General aromatization</TH>
</TR>-->
    <!--1,2-dihydropyridin-2-one-->
<tr>
    <td align="center">Molecule in aliphatic form</td>
    <td align="center">Basic aromatization</td>
    <td align="center">General aromatization</td>
</tr>
<tr><TD colspan="3" align="center" ><b>IUPAC name: </b>pyridin-2(1H)-one</TD></tr>
<TR>
<TD><IMG SRC="1.png" ALT="pyridone"></TD>
<TD><IMG SRC="1.png" ALT="pyridone with ChemAxon aromatization"></TD>
<TD><IMG SRC="1_d.png" ALT="pyridone with Daylight aromatization"></TD>
</TR>

<tr><TD colspan="3" align="center" ><b>IUPAC name: </b>2-thioxo-2,3-dihydropyrimidin-4(1H)-one</TD></tr>
<TR>
<TD><IMG SRC="2.png" ALT="smi 2"></TD>
<TD><IMG SRC="2.png" ALT=" with ChemAxon aromatization"></TD>
<TD><IMG SRC="2_d.png" ALT=" with Daylight aromatization"></TD>
</TR>

<tr><TD colspan="3" align="center" ><b>IUPAC name: </b>2,4-dihydro-3H-1,2,4-triazol-3-thione</TD></tr>
<TR>
<TD><IMG SRC="3.png" ALT="smi 3"></TD>
<TD><IMG SRC="3.png" ALT=" with ChemAxon aromatization"></TD>
<TD><IMG SRC="3_d.png" ALT=" with Daylight aromatization"></TD>
</TR>

<tr><TD colspan="3" align="center" ><b>IUPAC name: </b>9H-xanthen-9-one</TD></tr>
<TR>
<TD><IMG SRC="4.png" ALT="smi 4"></TD>
<TD><IMG SRC="4_c.png" ALT=" with ChemAxon aromatization"></TD>
<TD><IMG SRC="4_d.png" ALT=" with Daylight aromatization"></TD>
</TR>

<tr><TD colspan="3" align="center" ><b>IUPAC name: </b>5-thioxo-1,2,4-triazolidin-3-one</TD></tr>
<tr>
<TD><IMG SRC="5.png" ALT="smi 5"></TD>
<TD><IMG SRC="5.png" ALT=" with ChemAxon aromatization"></TD>
<TD><IMG SRC="5_d.png" ALT=" with Daylight aromatization"></TD>
</TR>
    
<tr><TD colspan="3" align="center" ><b>IUPAC name: </b>imidazo[1,5-a]pyridine-3(2H)-thione</TD></tr>
<tr>
<TD><IMG SRC="6.png" ALT="smi 6"></TD>
<TD><IMG SRC="6.png" ALT=" with ChemAxon aromatization"></TD>
<TD><IMG SRC="6_d.png" ALT=" with Daylight aromatization"></TD>
</Tr>
    
</table>

<h2><a class="anchor" NAME="queryArom">Aromatization of query structures</a></h2>
<h3><a class="anchor" NAME="queryAtoms">Structures with Query atoms</a></h3>
<P>
A query structure which defines one or more molecules with atom lists or
query atoms in one query structure 
is converted to aromatic form if any of the defined structures 
can be aromatized.
Link nodes, R-atoms and query bonds are not aromatized. If these features are 
used, the use of single/aromatic or double/aromatic bond types is 
recommended for each of the ring bonds in order to ensure matching to 
aromatic systems.

<table border="0" cellspacing="0" cellpadding="5" class="grid">
<tr>
    <td align="center">Query structure</td>
    <td align="center">Aromatized</td>
</tr>
<tr>
    <td align="center"><IMG SRC="7.png" ALT="smi 7"></td>
    <td align="center"><IMG SRC="../images/yes.png" ALT="yes"></td>
</tr>
<tr>
    <td align="center"><IMG SRC="8.png" ALT="smi 8"></td>
    <td align="center"><IMG SRC="../images/yes.png" ALT="yes"></td>
</tr>
<tr>
    <td align="center"><IMG SRC="9.png" ALT="smi 9"></td>
    <td align="center"><IMG SRC="../images/yes.png" ALT="yes"></td>
</tr>
<tr>
    <td align="center"><IMG SRC="10.png" ALT="smi 10"></td>
    <td align="center"><IMG SRC="../images/yes.png" ALT="yes"></td>
</tr>
<tr>
    <td align="center"><IMG SRC="11.png" ALT="smi 11"></td>
    <td align="center"><IMG SRC="../images/yes.png" ALT="yes"></td>
</tr>
<tr>
    <td align="center"><IMG SRC="12.png" ALT="smi 12"></td>
    <td align="center"><IMG SRC="../images/yes.png" ALT="yes"></td>
</tr>
<tr>
    <td align="center"><IMG SRC="13.png" ALT="smi 13"></td>
    <td align="center"><IMG SRC="../images/no.png" ALT="no"></td>
</tr>
</table>

<h3><a class="anchor" NAME="queryAtoms">Structures with Query bonds</a></h3>
<P>
Query structures with ANY bond are aromatized if 
the ring or ring system containing the ANY bond can be aromatized supposing 
the ANY bond as aromatic. In this case the single and double bonds are 
converted to single_or_aromatic and double_or_aromatic bonds respectively.<br>
Structures with query bonds may contain atoms with improper valence due to 
mixed aromatic-Kekule representation. These structures are accepted and 
aromatized as they are just an incomplete representation of an otherwise 
aromatic ring.

<table border="0" cellspacing="0" cellpadding="5" class="grid">
<tr>
    <td align="center">Query structure</td>
    <td align="center">Aromatized form</td>
</tr>
<tr>
    <td align="center"><IMG SRC="21.png" ALT="[#6]1~[#6]C=CC=C1"></td>
    <td align="center"><IMG SRC="22.png" ALT="query aromatized"></td>
</tr>
<tr>
    <td align="center"><IMG SRC="27.png" ALT="*~1~*-*~*~*~*~1"></td>
    <td align="center"><IMG SRC="28.png" ALT="query aromatized"></td>
</tr>
<tr>
    <td align="center"><IMG SRC="23.png" ALT="mixed aromatic-Kekule representation 1"></td>
    <td align="center"><IMG SRC="24.png" ALT="query aromatized"></td>
</tr>
<tr>
    <td align="center"><IMG SRC="25.png" ALT="mixed aromatic-Kekule representation 2"></td>
    <td align="center"><IMG SRC="26.png" ALT="query aromatized"></td>
</tr>
</table>

<h2>Aromatization error detection</h2>
Possible aromatization errors may be detected with the use of Structure Checker.
<a href="../structurechecker/checker.html">Guide to Aromaticity Error Checker.</a>

<h2>References</h2>
<table border="0" cellspacing="0" cellpadding="5">
<tr VALIGN=TOP>
<td>[1]</td>
<td><a HREF="http://www.daylight.com/dayhtml_tutorials/languages/smiles/index.html#AROM" TARGET="_top">http://www.daylight.com/dayhtml_tutorials/languages/smiles/index.html</a></td>
</tr>
<tr VALIGN=TOP>
<td>[2]</td>
<td><a HREF="http://www.chemaxon.com/forum/ftopic319.html" TARGET="_top">Open discussion forum about aromatic forms</a></td>
</tr>
<tr VALIGN=TOP>
<td>[3]</td>
<td><a HREF="http://www.mdl.com/" TARGET="_top">MDL's Enhanced Stereochemical Representation</a></td>
</tr>
</table>
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